Metabolic Fate of Losartan, a New Angiotensin II Receptor Antagonist. (2). Absorption, Distribution, Metabolism, Excretion and Effects on Drug Metabolizing Enzyme Activities after Repeated Oral Administration in Rats.

Abstract

The absorption, distribution, metabolism and excretion of losartan were investigated in male rats after repeated oral administration. The effects on liver weight, protein concentration and drug metabolizing enzyme activities were also examined.1. 14C-Losartan was administered to male rats at a dose of 10 mg/kg/day for 21 days. The plasma levels of radioactivity reached a steady state by 6th day, and the concentration at 72 hr after 21st dosing represented 10% of the corresponding Cmax of 1.9 μg eq./ml.2. Urinary or fecal excretion of radioactivity within 24 hr after each administration was similar. Within 72 hr after 21st dosing, approximately 2.1% and 94% of the total dose were excreted into urine and feces, respectively.3. Tissue distribution of 14C-losartan in non-fasting male rats was studied after 1st, 7th, 14th and 21st oral administration at a dose of 10 mg/kg/day. At 8 hr after 1st dosing, quantitative tissue analysis indicated that the highest levels of radioactivity were found in the liver, followed by the large intestine, cecum and kidney. In the other tissues, the radioactivity levels were lower than that in plasma. In all tissues, the radioactivity at 24 hr after the dosing decreased to less than 32% of the levels observed at 8 hr or were below the limit of detection. The radioactivity reached nearly steady state in the kidney after 7th dosing and in the lung after 14th dosing. The radioactivity in plasma and tissues progressively decreased with time up to 96 hr after the last dosing. However, the radioactivity was eliminated very slowly from aorta.4. A small amount of losartan was excreted in urine only after 6th dosing. The major metabolites in the urine were identified as M-10 and M-11. On the other hand, a large amount of losartan was excreted in feces, and M-1, M-2 and M-4 were also found. In liver and kidney samples at 8 hr after 1st and 21st dosing, losartan and M-4 were mainly found. No differences in urinary or fecal excretion of losartan and its metabolites were observed after 6th, 13th and 21st administration.5. At 24 hr and 2 weeks after repeated oral administration of losartan for 7 days at a dose of 10 mg/kg/day, losartan had no effect on liver weight, microsomal protein concentration and drug metabolizing enzyme activities in liver microsomes. On the other hand, as compared with control, a slight, but statistically significant decrease in the amount of cytochrome b5 and cytochrome P-450 was observed at 24 hr after repeated oral administration of losartan at a dose of 135 mg/kg/day, whereas no differences were observed at 2 weeks after repeated administration.